A small molecule significantly inhibits the bcr/abl fusion gene at the mRNA level in human chronic myelogenous leukemia

Leuk Res. 2011 Aug;35(8):1074-9. doi: 10.1016/j.leukres.2010.11.012. Epub 2010 Dec 15.

Abstract

Bcr/abl fusion gene is the marker gene in chronic myelogenous leukemia (CML) and becomes the target for CML therapy. Although Imatinib opened a new way to treat CML, the resistance to the drug caused by bcr/abl fusion protein mutation stimulated search for new molecules to inhibit bcr/abl expression. In our research, it was found that a novel 2-aminosteroid (H89465) possessed special mechanism in treating CML. H89465 inhibits the proliferation of both non-resistant and resistant CML cells such as K562, Meg-01 and clinical primary CML cells. It prolongs the survival time of NOD/SCID mice inoculated with K562 leukemia cells. The mechanism underlying the effects is concerned with down-regulation of bcr/abl mRNA expression followed by decreasing the BCR/ABL protein expression and tyrosine kinase activity in CML cells. Our results demonstrate that H89465 possesses the therapeutic potential in treating human CML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Down-Regulation
  • Drug Resistance, Neoplasm / drug effects*
  • Flow Cytometry
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / genetics
  • Humans
  • Immunoprecipitation
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / prevention & control*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • RNA, Messenger / antagonists & inhibitors*
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Steroids / chemical synthesis
  • Steroids / pharmacology*
  • Steroids / therapeutic use
  • Survival Rate
  • Tumor Cells, Cultured

Substances

  • H89465
  • RNA, Messenger
  • Steroids
  • Fusion Proteins, bcr-abl